International Veterinary Epilepsy Task Force consensus proposal: medical treatment of canine epilepsy in Europe

BMC Veterinary Research

Holger A. Volk⁹  Clare Rusbridge^1,13  Heidrun Potschka⁷  Michael Podell^1,17  Simon Platt^1,15  Edward E. Patterson^1,10  Akos Pakozdy^1,12  Kaspar Matiasek⁶  Paul J.J. Mandigers⁵  Wolfgang Löscher¹  Sam Long^1,19  Andrea Fischer²  Robyn G. Farquhar³  Mette Berendt^1,11  Andrea Tipold^1,14  Veronika M. Stein^1,14  Jacques Penderis^1,18  Karen Muñana⁸  Luisa De Risio⁴  Sofie F.M. Bhatti^1,16 

[1] Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Bünteweg 17, Hannover, 30559, Germany;Clinical Veterinary Medicine, Ludwig-Maximillians-University, Veterinärstr. 13, Munich, 80539, Germany;Fernside Veterinary Centre, 205 Shenley Road, Borehamwood, Hertfordshire, SG9 0TH, United Kingdom;Animal Health Trust, Lanwades Park, Kentford, Newmarket, Suffolk, CB8 7UU, United Kingdom;Department of Clinical Sciences of Companion Animals, Utrecht University, Yalelaan 108, Utrecht, 3583 CM, The Netherlands;Section of Clinical & Comparative Neuropathology, Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Veterinärstr. 13, Munich, 80539, Germany;Department of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximillians-University, Königinstr. 16, Munich, 80539, Germany;Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 1052 William Moore Drive, Raleigh 27607, NC, USA;Department of Clinical Science and Services, Royal Veterinary College, Hatfield AL9 7TA, Hertfordshire, UK;University of Minnesota College of Veterinary Medicine, D426 Veterinary Medical Center, 1352 Boyd Avenue, St. Paul 55108, MN, USA;Department of Veterinary and Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark;Clinical Unit of Internal Medicine Small Animals, University of Veterinary Medicine, Veterinärplatz 1, Vienna, 1210, Austria;School of Veterinary Medicine, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, GU2 7TE, United Kingdom;Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Bünteweg 9, Hannover, 30559, Germany;College of Veterinary Medicine, University of Georgia, 501 DW Brooks Drive, Athens 30602, GA, USA;Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke 9820, Belgium;Chicago Veterinary Neurology and Neurosurgery, 3123 N. Clybourn Avenue, Chicago 60618, IL, USA;Vet Extra Neurology, Broadleys Veterinary Hospital, Craig Leith Road, Stirling FK7 7LE, Stirlingshire, United Kingdom;University of Melbourne, 250 Princes Highway, Weibee 3015, VIC, Australia

关键词: Treatment;    Epilepsy;    Epileptic seizure;    Dog;   

Others  :  1224282
DOI  :  10.1186/s12917-015-0464-z

 received in 2015-06-04, accepted in 2015-06-29,  发布年份 2015

【 摘 要 】

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible.

【 授权许可】

   
2015 Bhatti et al.

【 图 表 】

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【 参考文献 】

• [1]Adusumalli VE, Gilchrist JR, Wichmann JK, Kucharczyk N, Sofia RD. Pharmacokinetics of felbamate in pediatric and adult beagle dogs. Epilepsia. 1992; 33:955-60.
• [2]Al-Tahan F, Frey HH. Absorption kinetics and bioavailability of phenobarbital after oral administration to dogs. J Vet Pharmacol Ther. 1985; 8:205-7.
• [3]Alves L, Hülsmeyer V, Jaggy A, Fischer A, Leeb T, Drögemüller M. Polymorphisms in the ABCB1 gene in phenobarbital responsive and resistant idiopathic epileptic Border Collies. J Vet Intern Med. 2011; 25:484-9.
• [4]Baird-Heinz HE, Van Schoick AL, Pelsor FR, Ranivand L, Hungerford LL. A systematic review of the safety of potassium bromide in dogs. J Am Vet Med Assoc. 2012; 240:705-15.
• [5]Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45.
• [6]Berendt M, Gredal H, Ersbøll AK, Alving J. Premature death, risk factors, and life patterns in dogs with epilepsy. J Vet Intern Med. 2007; 21:754-9.
• [7]Berendt M, Gredal H, Pedersen LG, Alban L, Alving J. A cross-sectional study of epilepsy in Danish Labrador Retrievers: prevalence and selected risk factors. J Vet Intern Med. 2002; 16:262-8.
• [8]Bialer M, Doose DR, Murthy B, Curtin C, Wang SS, Twyman RE et al.. Pharmacokinetic interactions of topiramate. Clin Pharmacokinet. 2004; 43:763-80.
• [9]Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. Clin Pharmacokinet. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. 2010;49:661-9.
• [10]Boothe DM, Dewey C, Carpenter DM. Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. J Am Vet Med Assoc. 2012; 240:1073-83.
• [11]Boothe DM, Perkins J. Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs. J Vet Pharmacol Ther. 2008; 31:544-53.
• [12]Bourgeois BF. Felbamate. Semin Pediatr Neurol. 1997; 4:3-8.
• [13]Bunch SE, Castleman WL, Hornbuckle WE, Tennant BC. Hepatic cirrhosis associated with long-term anticonvulsant drug therapy in dogs. J Am Vet Med Assoc. 1982; 181:357-62.
• [14]Cahan LD, Engel J. Surgery for epilepsy: a review. Acta Neurol Scand. 1986; 73:551-60.
• [15]Caldwell GW, Wu WN, Masucci JA, McKown LA, Gauthier D, Jones WJ et al.. Metabolism and excretion of the antiepileptic/antimigraine drug, Topiramate in animals and humans. Eur J Drug Metab Pharmacokinet. 2005; 30:151-64.
• [16]Chadwick DW. The treatment of the first seizure: the benefits. Epilepsia. 2008; 49:26-8.
• [17]Charalambous M, Brodbelt D, Volk HA. Treatment in canine epilepsy--a systematic review. BMC Vet Res. 2014; 10:257.
• [18]Chung JY, Hwang CY, Chae JS, Ahn JO, Kim TH, Seo KW et al.. Zonisamide monotherapy for idiopathic epilepsy in dogs. N Z Vet J. 2012; 60:357-9.
• [19]Contin M1, Albani F, Riva R, Baruzzi A. Levetiracetam therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs. Ther Drug Monit. 2004; 26:375-9.
• [20]Cook AK, Allen AK, Espinosa D, Barr J. Renal tubular acidosis associated with zonisamide therapy in a dog. J Vet Intern Med. 2011; 25:1454-7.
• [21]Daminet S, Ferguson DC. Influence of drugs on thyroid function in dogs. J Vet Intern Med. 2003; 17:463-72.
• [22]Dayrell-Hart B, Steinberg SA, VanWinkle TJ, Farnbach GC. Hepatotoxicity of phenobarbital in dogs: 18 cases (1985-1989). J Am Vet Med Assoc. 1991; 199:1060-6.
• [23]De Risio L. Chapter 12-20. In: Canine and feline epilepsy. Diagnosis and Management. 2014.347-475.
• [24]De Risio L, Freeman J, Shea A. Proceedings of the 27th Symposium of the European College of Veterinary Neurology, Madrid, 18-20 September 2014, and Journal of Veterinary Internal Medicine 2015; Prevalence and clinical characteristics of idiopathic epilepsy in the Italian Spinone in the UK.
• [25]Dewey CW. Anticonvulsant therapy in dogs and cats. Vet Clin North Am Small Anim Pract. 2006; 36:1107-27.
• [26]Dewey CW, Barone G, Smith K, Kortz GD. Alternative anticonvulsant drugs for dogs with seizure disorders. Vet Med. 2004;99:786–93.
• [27]Dewey CW, Cerda-Gonzalez S, Levine JM, Badgley BL, Ducoté JM, Silver GM et al.. Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy. J Am Vet Med Assoc. 2009; 235:1442-9.
• [28]Dewey CW, Guiliano R, Boothe DM, Berg JM, Kortz GD, Joseph RJ et al.. Zonisamide therapy for refractory idiopathic epilepsy in dogs. J Am Anim Hosp Assoc. 2004; 40:285-91.
• [29]Elterman RD, Glauser TA, Wyllie E, Reife R, Wu SC, Pledger G. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group. Neurology. 1999; 52:1338-44.
• [30]European Medicines agency . http://www. [http:/ / www.ema.europa.eu/ ema/ index.jsp?curl=pages/ medicines/ veterinary/ medicines/ 002543/ vet_med_000268.jsp&mid=WC0b01ac0580 08d7a8] webciteema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/veterinary/002543/WC500140840.pdf webcite
• [31]Farnbach GC. Serum concentrations and efficacy of phenytoin, phenobarbital, and primidone in canine epilepsy. J Am Vet Med Assoc. 1984; 184:1117-20.
• [32]Fischer A, Jurina K, Potschka H, Rentmeister K, Tipold A, Volk HA et al.. Hoofdstuk 4: Therapie. Idiopathische epilepsie bij de hond. 2013.69-115.
• [33]Forrester SD, Wilcke JR, Jacobson JD, Dyer KR. Effects of a 44-day administration of phenobarbital on disposition of clorazepate in dogs. Am J Vet Res. 1993; 54:1136-8.
• [34]Freitag H, Tuxhorn I. Cognitive function in preschool children after epilepsy surgery: rationale for early intervention. Epilepsia. 2005; 46:561-7.
• [35]Frey HH. Use of anticonvulsants in small animals. Vet Rec. 1986; 118:484-6.
• [36]Frey HH, Göbel W, Löscher W. Pharmacokinetics of primidone and its active metabolites in the dog. Arch Int Pharmacodyn Ther. 1979; 242:14-30.
• [37]Garnett WR. Clinical pharmacology of topiramate: a review. Epilepsia. 2000; 41:61-5.
• [38]Gaskill CL, Cribb AE. Pancreatitis associated with potassium bromide/phenobarbital combination therapy in epileptic dogs. Can Vet J. 2000; 41:555-8.
• [39]Gaskill CL, Miller LM, Mattoon JS, Hoffmann WE, Burton SA, Gelens HC et al.. Liver histopathology and liver and serum alanine aminotransferase and alkaline phosphatase activities in epileptic dogs receiving phenobarbital. Vet Pathol. 2005; 42:147-60.
• [40]Gieger TL, Hosgood G, Taboada J, Wolfsheimer KJ, Mueller PB. Thyroid function and serum hepatic enzyme activity in dogs after phenobarbital administration. J Vet Intern Med. 2000; 14:277-81.
• [41]Gieger TL, Hosgood G, Taboada J, Wolfsheimer KJ, Mueller PB. Thyroid function and serum hepatic enzyme activity in dogs after phenobarbital administration. J Vet Intern Med. 2000; 14:277-81.
• [42]Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C et al.. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2006; 47:1094-120.
• [43]Glauser TA, Loddenkemper T. Management of childhood epilepsy. Epilepsy. 2013; 19:568.
• [44]Govendir M, Perkins M, Malik R. Improving seizure control in dogs with refractory epilepsy using gabapentin as an adjunctive agent. Aust Vet J. 2005; 83:602-8.
• [45]Gulløv CH, Toft N, Berendt M. A Longitudinal Study of Survival in Belgian Shepherds with Genetic Epilepsy. J Vet Int Med. 2012; 26:1115-20.
• [46]Hess RS, Kass PH, Shofer FS, Van Winkle TJ, Washabau RJ. Evaluation of risk factors for fatal acute pancreatitis in dogs. J Am Vet Med Assoc. 1999; 214:46-51.
• [47]Heynold Y, Faissler D, Steffen F, Jaggy A. Clinical, epidemiological and treatment results of idiopathic epilepsy in 54 labrador retrievers: a long-term study. J Small Anim Pract. 1997; 38:7-14.
• [48]Hojo T, Ohno R, Shimoda M, Kokue E. Enzyme and plasma protein induction by multiple oral administrations of phenobarbital at a therapeutic dosage regimen in dogs. J Vet Pharmacol Ther. 2002; 25:121-7.
• [49]Hülsmeyer V, Zimmermann R, Brauer C, Sauter-Louis C, Fischer A. Epilepsy in Border Collies: clinical manifestation, outcome, and mode of inheritance. J Vet Intern Med. 2010; 24:171-8.
• [50]Hussein G, Troupin AS, Montouris G. Gabapentin interaction with felbamate. Neurology. 1996; 47:1106.
• [51]Jacobs G, Calvert C, Kaufman A. Neutropenia and thrombocytopenia in three dogs treated with anticonvulsants. J Am Vet Med Assoc. 1998; 212:681-4.
• [52]Janszky J, Janszky I, Schulz R, Hoppe M, Behne F, Pannek HW et al.. Temporal lobe epilepsy with hippocampal sclerosis: predictors for long-term surgical outcome. Brain. 2005; 128:395-404.
• [53]Johannessen SI. Pharmacokinetics and interaction profile of topiramate: review and comparison with other newer antiepileptic drugs. Epilepsia. 1997; 38:18-23.
• [54]Jull P, Risio LD, Horton C, Volk HA. Effect of prolonged status epilepticus as a result of intoxication on epileptogenesis in a UK canine population. Vet Rec. 2011; 169:361.
• [55]Kaufman DW, Kelly JP, Anderson T, Harmon DC, Shapiro S. Evaluation of case reports of aplastic anemia among patients treated with felbamate. Epilepsia. 1997; 38:1265-9.
• [56]Khoutorsky A, Bruchim Y. Transient leucopenia, thrombocytopenia and anaemia associated with severe acute phenobarbital intoxication in a dog. J Small Anim Pract. 2008; 49:367-9.
• [57]Kiviranta AM, Laitinen-Vapaavuori O, Hielm-Björkman A, Jokinen T. Topiramate as an add-on antiepileptic drug in treating refractory canine idiopathic epilepsy. J Small Anim Pract. 2013; 54:512-20.
• [58]Kube SA, Vernau KM, LeCouteur RA. Dyskinesia associated with oral phenobarbital administration in a dog. J Vet Intern Med. 2006; 20:1238-40.
• [59]Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000; 342:314-9.
• [60]La Roche SM, Helmers SL. The new antiepileptic drugs: scientific review. JAMA. 2004; 291:605-14.
• [61]Leppik IE. Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure. 2004; 13:5-9.
• [62]Levitski RE, Trepanier öA. . Effect of timing of blood collection on serum phenobarbital concentrations in dogs with epilepsy. J Am Vet Med Assoc. 2000; 15(217):200-4.
• [63]Löscher W, Potschka H, Rieck S, Tipold A, Rundfeldt C. Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. Epilepsia. 2004; 45:1228-39.
• [64]Löscher W, Potschka H, Rieck S, Tipold A, Rundfeldt C. Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. Epilepsia. 2004; 45:1228-39.
• [65]Lyseng-Williamson KA, Yang LP. Topiramate: a review of its use in the treatment of epilepsy. Drugs. 2007; 67:2231-56.
• [66]March PA, Hillier A, Weisbrode SE, Mattoon JS, Johnson SE, DiBartola SP et al.. Superficial necrolytic dermatitis in 11 dogs with a history of phenobarbital administration (1995-2002). J Vet Intern Med. 2004; 18:65-74.
• [67]March PA, Podell M, Sams RA. Pharmacokinetics and toxicity of bromide following high-dose oral potassium bromide administration in healthy Beagles. J Vet Pharmacol Ther. 2002; 25:425-32.
• [68]Martinez SE, Bowen KA, Remsberg CM, Takemoto JK, Wright HM, Chen-Allen AV et al.. High-performance liquid chromatographic analysis of lacosamide in canine serum using ultraviolet detection: application to pre-clinical pharmacokinetics in dogs. Biomed Chromatogr. 2012; 26:606-9.
• [69]Miller ML, Center SA, Randolph JF, Lepherd ML, Cautela MA, Dewey CW. Apparent acute idiosyncratic hepatic necrosis associated with zonisamide administration in a dog. J Vet Intern Med. 2011; 25:1156-60.
• [70]Monteiro R, Anderson TJ, Innocent G, Evans NP, Penderis J. Variations in serum concentration of phenobarbitone in dogs receiving regular twice daily doses in relation to the times of administration. Vet Rec. 2009; 165:556-8.
• [71]Montouris GD, Biton V, Rosenfeld WE. Nonfocal generalized tonic-clonic seizures: response during long-term topiramate treatment. Topiramate YTC/YTCE Study Group. Epilepsia. 2000; 41:77-81.
• [72]Moore SA, Muñana KR, Papich MG, Nettifee-Osborne JA. The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital. J Vet Pharmacol Ther. 2011; 34:31-4.
• [73]Moore SA, Muñana KR, Papich MG, Nettifee-Osborne JA. The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital. J Vet Pharmacol Ther. 2011; 34:31-4.
• [74]Morton DJ, Honhold N. Effectiveness of a therapeutic drug monitoring service as an aid to the control of canine seizures. Vet Rec. 1988; 9(122):346-9.
• [75]Müller PB, Taboada J, Hosgood G, Partington BP, VanSteenhouse JL, Taylor HW et al.. Effects of long-term phenobarbital treatment on the liver in dogs. J Vet Intern Med. 2000; 14:165-71.
• [76]Muñana KR. Update: seizure management in small animal practice. Vet Clin North Am Small Anim Pract. 2013; 43:1127-47.
• [77]Muñana KR, Nettifee-Osborne JA, Bergman RL, Mealey KL. Association between ABCB1 genotype and seizure outcome in Collies with epilepsy. J Vet Intern Med. 2012; 26:1358-64.
• [78]Muñana KR, Nettifee-Osborne JA, Papich MG. Effect of chronic administration of phenobarbital, or bromide, on pharmacokinetics of levetiracetam in dogs with epilepsy. J Vet Intern Med. 2015. In press.
• [79]Muñana KR, Thomas WB, Inzana KD, Nettifee-Osborne JA, McLucas KJ, Olby NJ et al.. Evaluation of levetiracetam as adjunctive treatment for refractory canine epilepsy: a randomized, placebo-controlled, crossover trial. J Vet Intern Med. 2012; 26:341-8.
• [80]Nichols ES, Trepanier LA, Linn K. Bromide toxicosis secondary to renal insufficiency in an epileptic dog. J Am Vet Med Assoc. 1996; 208:231-3.
• [81]O'Dell C, Shinnar S. Initiation and discontinuation of antiepileptic drugs. Neurol Clin. 2001; 19:289-311.
• [82]Orito K, Saito M, Fukunaga K, Matsuo E, Takikawa S, Muto M et al.. Pharmacokinetics of zonisamide and drug interaction with phenobarbital in dogs. J Vet Pharmacol Ther. 2008; 31:259-64.
• [83]Packer RMA, Nye G, Porter SE, Vok HA. Assessment into the usage of levetiracetam in a canine epilepsy clinic. BMC Vet Res. 2015. In press.
• [84]Packer RM, Shihab NK, Torres BB, Volk HA. Clinical risk factors associated with anti-epileptic drug responsiveness in canine epilepsy. PLoS One. 2014; 25:9.
• [85]Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet. 2004; 43:707-24.
• [86]Patterson EE, Goel V, Cloyd JC, O'Brien TD, Fisher JE, Dunn AW et al.. Intramuscular, intravenous and oral levetiracetam in dogs: safety and pharmacokinetics. J Vet Pharmacol Ther. 2008; 31:253-8.
• [87]Pedersoli WM, Wike JS, Ravis WR. Pharmacokinetics of single doses of phenobarbital given intravenously and orally to dogs. Am J Vet Res. 1987; 48:679-83.
• [88]Pellock JM, Faught E, Leppik IE, Shinnar S, Zupanc ML. Felbamate: consensus of current clinical experience. Epilepsy Res. 2006; 71:89-101.
• [89]Platt SR, Adams V, Garosi LS, Abramson CJ, Penderis J, De Stefani A et al.. Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy. Vet Rec. 2006; 59:881-4.
• [90]Podell M. Antiepileptic drug therapy. Clin Tech Small Anim Pract. 1998; 13:185-92.
• [91]Podell M. Chapter 7. In: BSAVA Manual of Canine and Feline Neurology. 2010.97-112.
• [92]Podell M. Antiepileptic drug therapy and monitoring. Top Companion Anim Med. 2013; 28:59-66.
• [93]Podell M, Fenner WR. Bromide therapy in refractory canine idiopathic epilepsy. J Vet Intern Med. 1993; 7:318-27.
• [94]Potschka H, Fischer A, Löscher W, Patterson EE, Bhatti SFM, Berendt M, De Risio L, Farquhar RG, Long S, Mandigers PJJ, Matiasek K, Muñana K, Pakozdy A, Penderis J, Platt S, Podell M, Pumarola MB, Rusbridge C, Stein VM, Tipold A, Volk HA21. International Veterinary Epilepsy Task Force Consensus Proposal: Outcome of therapeutic interventions in canine and feline epilepsy. BMC Vet Res; 2015.
• [95]Radulovic LL, Türck D, von Hodenberg A, Vollmer KO, McNally WP, DeHart PD et al.. Disposition of gabapentin (neurontin) in mice, rats, dogs, and monkeys. Drug Metab Dispos. 1995; 23:441-8.
• [96]Ravis WR, Nachreiner RF, Pedersoli WM, Houghton NS. Pharmacokinetics of phenobarbital in dogs after multiple oral administration. Am J Vet Res. 1984; 45:1283-6.
• [97]Ravis WR, Pedersoli WM, Wike JS. Pharmacokinetics of phenobarbital in dogs given multiple doses. Am J Vet Res. 1989; 50:1343-7.
• [98]Rieck S, Rundfeldt C, Tipold A. Anticonvulsant activity and tolerance of ELB138 in dogs with epilepsy: a clinical pilot study. Vet J. 2006; 172:86-95.
• [99]Rogawski MA, Johnson MR. Intrinsic severity as a determinant of antiepileptic drug refractoriness. Epilepsy Curr. 2008; 8:127-30.
• [100]Ruehlmann D, Podell M, March P. Treatment of partial seizures and seizure-like activity with felbamate in six dogs. J Small Anim Pract. 2001; 42:403-8.
• [101]Rundfeldt C, Gasparic A, Wlaź P. Imepitoin as novel treatment option for canine idiopathic epilepsy: pharmacokinetics, distribution, and metabolism in dogs. J Vet Pharmacol Ther. 2014; 37:421-34.
• [102]Rundfeldt C, Löscher W. The pharmacology of imepitoin: the first partial benzodiazepine receptor agonist developed for the treatment of epilepsy. CNS Drugs. 2014; 28:29-43.
• [103]Salazar V, Dewey CW, Schwark W, Badgley BL, Gleed RD, Horne W et al.. Pharmacokinetics of single-dose oral pregabalin administration in normal dogs. Vet Anaesth Analg. 2009; 36:574-80.
• [104]Schwartz M, Muñana KR, Olby NJ. Possible drug-induced hepatopathy in a dog receiving zonisamide monotherapy for treatment of cryptogenic epilepsy. J Vet Med Sci. 2011; 73:1505-8.
• [105]Schwartz-Porsche D, Löscher W, Frey HH. Therapeutic efficacy of phenobarbital and primidone in canine epilepsy: a comparison. J Vet Pharmacol Ther. 1985; 8:113-9.
• [106]Scola N, Kaczmarczyk J, Möllenhoff K. Infantile bromoderma due to antiepileptic therapy. J Dtsch Dermatol Ges. 2012; 10:131-2.
• [107]Shaik IH, Mehvar R. Cytochrome P450 induction by phenobarbital exacerbates warm hepatic ischemia-reperfusion injury in rat livers. Free Radic Res. 2010; 44:441-53.
• [108]Shih JJ, Ochoa JG. A systematic review of antiepileptic drug initiation and withdrawal. Neurologist. 2009; 15:122-31.
• [109]Shih JJ, Ochoa JG. A systematic review of antiepileptic drug initiation and withdrawal. Neurologist. 2009; 15:122-31.
• [110]Shorvon SD. Safety of topiramate: adverse events and relationships to dosing. Epilepsia. 1996; 37:18-S22.
• [111]Shorvon S, Luciano AL. Prognosis of chronic and newly diagnosed epilepsy: revisiting temporal aspects. Curr Opin Neurol. 2007; 20:208-12.
• [112]Sills GJ. The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol. 2006; 6:108-13.
• [113]Speciale J, Dayrell-Hart B, Steinberg SA. Clinical evaluation of c-vinyl-c-aminobutyric acid for control of epilepsy in dogs. J Am Vet Med Assoc. 1991; 198:995-1000.
• [114]Steinberg MFD. Levetiracetam therapy for long-term idiopathic epileptic dogs. J Vet Intern Med. 2004; 18:410.
• [115]Stephen LJ, Brodie MJ. Selection of antiepileptic drugs in adults. Neurologic Clinics. 2009; 27:967-992.
• [116]Streeter AJ, Stahle PL, Holland ML, Pritchard JF, Takacs AR. Pharmacokinetics and bioavailability of topiramate in the beagle dog. Drug Metab Dispos. 1995; 23:90-3.
• [117]Sutula TP, Hagen J, Pitkänen A. Do epileptic seizures damage the brain? Curr Opin Neurol. 2003; 16:189-95.
• [118]Taverna M, Nguyet TT, Valentin C, Level O, Merry T, Kolbe HV et al.. A multi-mode chromatographic method for the comparison of the N-glycosylation of a recombinant HIV envelope glycoprotein (gp160s-MN/LAI) purified by two different processes. J Biotechnol. 1999; 68:37-48.
• [119]Thomas WB. Seizures and narcolepsy. In: A practical guide to canine and feline neurology. Dewey CW, editor. Iowa State Press (Blackwell Publishing), Ames (IA); 2003: p.193-212.
• [120]Thomas WB. Idiopathic epilepsy in dogs and cats. Vet Clin North Am Small Anim Pract. 2010; 40:161-79.
• [121]Thurman GD, McFadyen ML, Miller R. The pharmacokinetics of phenobarbitone in fasting and non-fasting dogs. J S Afr Vet Assoc. 1990; 61:86-9.
• [122]Tipold A, Keefe TJ, Löscher W, Rundfeldt C, de Vries F. Clinical efficacy and safety of imepitoin in comparison with phenobarbital for the control of idiopathic epilepsy in dogs. J Vet Pharmacol Ther. 2015; 38:160-8.
• [123]Trepanier LA. Use of bromide as an anticonvulsant for dogs with epilepsy. J Am Vet Med Assoc. 1995; 207:163-6.
• [124]Trepanier LA, Babish JG. Effect of dietary chloride content on the elimination of bromide by dogs. Res Vet Sci. 1995; 58:252-5.
• [125]Trepanier LA, Babish JG. Pharmacokinetic properties of bromide in dogs after the intravenous and oral administration of single doses. Res Vet Sci. 1995; 58:248-51.
• [126]Trepanier LA, Van Schoick A, Schwark WS, Carrillo J. Therapeutic serum drug concentrations in epileptic dogs treated with potassium bromide alone or in combination with other anticonvulsants: 122 cases (1992-1996). J Am Vet Med Assoc. 1998; 213:1449-53.
• [127]Volk HA, Matiasek LA, Luján Feliu-Pascual A, Platt SR, Chandler KE. The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. Vet J. 2008; 176:310-9.
• [128]von Klopmann T, Boettcher IC, Rotermund A, Rohn K, Tipold A. Euthyroid sick syndrome in dogs with idiopathic epilepsy before treatment with anticonvulsant drugs. J Vet Intern Med. 2006; 20:516-22.
• [129]von Klopmann T, Rambeck B, Tipold A. Prospective study of zonisamide therapy for refractory idiopathic epilepsy in dogs. J Small Anim Pract. 2007; 48:134-8.
• [130]Wagner SO, Sams RA, Podell M. Chronic phenobarbital therapy reduces plasma benzodiazepine concentrations after intravenous and rectal administration of diazepam in the dog. J Vet Pharmacol Ther. 1998; 21:335-41.
• [131]Weiss KL, Schroeder CE, Kastin SJ, Gibson JP, Yarrington JT, Heydorn WE et al.. MRI monitoring of vigabatrin-induced intramyelinic edema in dogs. Neurology. 1994; 44:1944-9.
• [132]Weissl J, Hülsmeyer V, Brauer C, Tipold A, Koskinen LL, Kyöstilä K et al.. Disease progression and treatment response of idiopathic epilepsy in Australian Shepherd dogs. J Vet Intern Med. 2012; 26:116-25.
• [133]White HS. Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia. 1999;40.
• [134]White HS, Harmsworth WL, Sofia RD, Wolf HH. Felbamate modulates the strychnine-insensitive glycine receptor. Epilepsy Res. 1995; 20:41-8.
• [135]Wilensky AJ, Friel PN, Levy RH, Comfort CP, Kaluzny SP. Kinetics of phenobarbital in normal subjects and epileptic patients. Eur J Clin Pharmacol. 1982; 23:87-92.
• [136]Wong IC, Lhatoo SD. Adverse reactions to new anticonvulsant drugs. Drug Saf. 2000; 23:35-56.
• [137]Wright HM, Chen AV, Martinez SE, Davies NM. Pharmacokinetics of oral rufinamide in dogs. J Vet Pharmacol Ther. 2012; 35:529-33.
• [138]Yarrington JT, Gibson JP, Dillberger JE, Hurst G, Lippert B, Sussman NM et al.. Sequential neuropathology of dogs treated with vigabatrin, a GABA-transaminase inhibitor. Toxicol Pathol. 1993; 21:480-9.
• [139]Zhang X, Velumian AA, Jones OT, Carlen PL. Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia. 2000;41.